Cancer is becoming the deadliest “killer” to human beings. In recent years, the total number of people died for cancer is close to 2 million each year in China. Although a variety of discovery of treatment pathways and drugs have brought hope for cancer patients, these conventional treatments still have many drawbacks, such as large side effect, poor treatment effect, tumor recurrence, metastasis and so on. There is an urgent need for new treatment techniques to improve the low success rate of cancer treatment. The recent emergence of individualized chemotherapy and targeted therapy has brought new hope to lung cancer treatment. Tumor molecular targeted therapy is a treatment method in which the key molecules that closely relate to the tumor growth will selectively kill the tumor cells through chemical or biological means. Targeted therapy has many characteristics, such as high specificity, high selectivity and mild side effects. When targeted therapy is used in combination with traditional chemotherapy, radiotherapy or tumor immunization, the efficacy can be greatly enhanced and the postoperative recurrence can be reduced. Tumor targeted therapy has rapidly develop in recent years, and becomes the emerging field of cancer treatment and future development trend.
Protein tyrosine kinases (PTKs) are a class of protein enzymes that can catalyze the phenolic hydroxyl phosphorylation on tyrosine residue of a variety of important proteins, thereby activating the biological activity of functional proteins. This reaction process plays a very important role in the intracellular signal transduction pathway, for it regulates a series of physiological and chemical processes such as cell growth, differentiation and death. Protein tyrosine kinase dysfunction can cause a series of diseases in the body. There are many studies showing that the activation of more than half of the original cancer gene and oncogene are associated with protein tyrosine kinase, and protein tyrosine kinase abnormal expression can lead to disorders of cell proliferation regulation, thereby leading to tumor genesis. In addition, tyrosine kinase abnormal expression is also closely associated with tumor invasion and metastasis, tumor neovascularization, tumor resistance to chemotherapy. Tyrosine kinase has become a very important target for the development of antitumor drugs.
Epidermal growth factor receptor (EGFR) is a receptor tyrosine protein kinase, and a transmembrane protein in the ErbB receptor family.
EGFR regulates proliferation, survival, adhesion, migration and differentiation of cells, which is hyperactivated or sustained in a variety of tumor cells, such as lung cancer cells, breast cancer cells, prostate cancer cells and the like. Abnormal activation of EGFR plays a key role in tumor transformation and growth. Blocking activation of EGFR has been clinically proven as one of the effective targeted therapy methods for tumor cell. EGFR was expressed in 50% of NSCLC (non-small cell lung cancer) cases, which makes EGFR and family members thereof a major candidate for targeted therapy. Gefitinib and erlotinib are the first generation of small molecule inhibitors of EGFR, and primarily used as drugs for treating advanced NSCLC. Clinical results show that gefitinib or erlotinib has effect on about 10% of white NSCLC and about 35% of Asian NSCLC patients. The analysis shows that the response rate to EGFR-tyrosine kinase inhibitor (TKI) in most NSCLC patients with EGFR activation mutations was significantly higher than that in EGFR wild type of NSCLC patients.
However, clinical studies have shown that many patients soon (12-14 months) have been resistant to these small molecule inhibitors of EGFR, ie, acquired drug resistance. Gatekeeper residue of T790M mutation is a mutation point in EGFR 20 eon and is one of the major mechanisms leading to drug resistance. Studies on a new generation of inhibitor for these EGFR mutations have recently been very successful. Afatinib is a potent and irreversible double inhibitor of EGFR and human epidermal growth factor receptor 2 (HER2) tyrosine kinases. Other similar multi-target, highly active and irreversible inhibitors, such as canertinib, and dacomitibib are also in later clinical trials. These novel second-generation irreversible inhibitors have a strong inhibitory effect on EGFR with L858R and T790M mutants, and have a significant effect on gefitinib or erlotinib-resistant cancer patients. However, these second-generation EGFR mutant inhibitors also have a strong inhibitory effect on wild-type EGFR (WT-EGFR). Clinical studies have shown that the inhibition of wild-type EGFR can lead to drug toxicity and side effects in most patients, such as rash or diarrhea in the human body.
In order to overcome the toxicity and side effects of the second-generation EGFR inhibitors, it is necessary to reduce the inhibitory effect on wild-type EGFR (WT-EGFR). A new generation (i.e. the third generation) of EGFR inhibitors should remain a strong inhibition against EGFR L858R activated mutants, Exon19 deletion activated mutants and T790M resistant mutants, and show a relatively low inhibitory effect on WT-EGFR and other tyrosine protein kinase receptors. Such compounds can be used not only in the treatment of cancer patients with a resistance to EGFR L858R-activated mutants and Exon19 deletion-activated mutants, but also in the treatment of cancer patients with EGFR-T790M resistant mutants resulting to the resistance against the first-generation EGFR inhibitors such as gefitinib, erlotinib or icotinib. The third-generation EGFR inhibitor, AZD9291, has a beneficial clinical effect, but its major metabolite, AZ5104, has a strong inhibitory effect on wild-type EGFR (WT-EGFR), which is the most probable incentive inducing the most common side effects such as a clinically common rash, diarrhea and the like.
The present invention shows many pyrimidine or pyridine compounds that have a high inhibitory activity against EGFR mutant(s), but only relatively low inhibitory effects on wild-type EGFR. The compounds of the present invention have good physicochemical properties and safety toxicity parameters. Such compounds will have a better effect in the treatment of cancer with EGFR-activated mutants and/or EGFR-resistant mutations.
The present invention relates to certain pyrimidine or pyridine compounds and pharmaceutically acceptable salt thereof; and can be used for the treatment or prevention of the disease or condition mediated by some mutated forms of epidermal growth factor receptors (e.g., L858R activated mutants, Exon19 deletion activated mutants, and T790M resistant mutants). Such compounds and pharmaceutically acceptable salts, stereoisomers, prodrugs and solvates thereof can be used for the treatment or prevention of many different cancers. The present invention also relates to a pharmaceutical composition comprising the compound and a pharmaceutically acceptable salt, stereoisomer, prodrug and solvate thereof; in particular, the useful polymorphs of the compound and salt; the useful intermediates used for preparing the said compounds; and the method for the treating diseases mediated by EGFR in the form of activated and/or resistant mutants by the compounds, pharmaceutically acceptable salts, stereoisomers, prodrugs and solvates thereof.
Therefore, there is an urgent need for a new type of compound, especially a compound with novel skeleton, to solve problems such as poor resistance, poor selectivity and the like. In the following list of documents, the patent or non-patent documents (journals, magazines, manuals and books, etc.) that are closest to patent applications are cited:    1. New England Journal of medicine, 2008, vol. 358, pp. 1160-1174;    2. Chemical and Biophysical Research Communications, 2004, vol. 319, pp. 1-11;    3. Science, 2004, vol. 304, pp. 1497-1500;    4. New England Journal of medicine, 2004, vol. 350, pp. 2129-2139;    5. Molecular Cancer Therapeutics, 2014, vol. 13, pp. 1468-1479;    6. Journal of Medicinal Chemistry, 2014, vol. 57, pp. 8249-8267;    7. WO2013014448A1, corresponding to CN103702990A;    8. WO2013108754A1;    9. CN103374000A;    10. CN103804303A;    11. WO2013184766A1; and    12. WO2009051822A1.
It should be stated that the above-mentioned patent or non-patent documents is only representative documents and are not a complete list of all the relevant literature. The entire disclosure of the above-mentioned patent or non-patent document is hereby incorporated in its entirety for a reference, and in the cases where there is a conflict, the description in the present application document shall prevail.
The current EGFR-TKI does still not solve the clinical problems caused by drug resistance, and the most of existing drugs are EGFR reversible or irreversible inhibitors based on quinazoline or quinolinamine as the basic nucleus, and they are still inevitably brought to the side effects of poor selectivity to EGFR wild-type cells. Therefore, there is an urgent need for a new type of compounds, especially compounds with novel skeletons, so as to solve problems such as poor drug resistance and selectivity.